Controlled release delivery of penciclovir via a silicone (MED-4750) polymer: kinetics of drug delivery and efficacy in preventing primary feline herpesvirus infection in culture

Abstract

BackgroundHerpesviruses are ubiquitous pathogens that infect and cause recurrent disease in multiple animal species. Feline herpesvirus-1 (FHV-1), a member of the alphaherpesvirus family, causes respiratory illness and conjunctivitis, and approximately 80% of domestic cats are latently infected. Oral administration of famciclovir or topical application of cidofovir has been shown in masked, placebo-controlled prospective trials to reduce clinical signs and viral shedding in experimentally inoculated cats. However, to the authors’ knowledge, other drugs have not been similarly assessed or were not safe or effective. Likewise, to our knowledge, no drugs have been assessed in a placebo-controlled manner in cats with recrudescent herpetic disease. Controlled-release devices would permit long-term administration of these drugs and enhance compliance.MethodsWe therefore engineered implantable cylindrical devices made from silicone (MED-4750) impregnated with penciclovir, for long-term, steady-state delivery of this drug.ResultsOur data show that these devices release penciclovir with a burst of drug delivery until the tenth day of release, then at an average rate of 5.063 ± 1.704 μg per day through the next 50 days with near zero-order kinetics (in comparison to MED-4750-acyclovir devices, which show the same burst kinetics and average 2.236 ± 0.625 μg/day thereafter). Furthermore, these devices suppress primary infection of FHV-1 in a cell culture system.ConclusionsThe clinical deployment of these silicone-penciclovir devices may allow long-term treatment of FHV-1 infection with a single intervention that could last the life of the host cat.

Pilot Study of the Safety and Tolerability of a Subconjunctival Penciclovir Implant in Cats Experimentally Infected with Herpesvirus

“…As a result, comparison of tear penciclovir concentrations across time points was possible. Tear penciclovir concentrations tended to be highest 1 week after implantation, suggesting a ''burst release'' from the implants that is consistent with previous in vitro studies of similar implants impregnated with acyclovir 33,50 or penciclovir. 32 However, it is possible that tear penciclovir concentrations in this study were also affected by conjunctival wound healing following implantation and initially, high tear penciclovir concentrations represented leakage through the surgical incision, with subsequent reductions due to wound closure and fibrosis.…”

“…The conjunctiva was closed using 6-0 polyglactin in a simple continuous pattern. Median (range) surgical time for both eyes was 35 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) min. Neomycin-polymyxinbacitracin ophthalmic ointment was placed in both eyes twice daily for 5-6 days following implant placement.…”

“…This implant was previously used to deliver acyclovir subcutaneously to mice inoculated with HSV-1, 32 and, in in vitro experiments, it has been demonstrated to release penciclovir and suppress replication of FHV-1. 33 However, to the authors' knowledge, there are no reports of use of penciclovir-containing implants for treatment of herpetic ocular surface disease in any animals experimentally infected with their speciesspecific herpesvirus. As such, this study is exploratory in nature and provides some early descriptive observations regarding the safety and tolerability of penciclovir delivered by this implant in a novel species and at a novel tissue site.…”

Volatile Acid-Solvent Evaporation (VASE): Molecularly Homogeneous Distribution of Acyclovir in a Bioerodable Polymer Matrix for Long-Term Treatment of Herpes Simplex Virus-1 Infections

“…Both the formic acid and acetonitrile were allowed to evaporate overnight and thoroughly dried as above. The resulting powder was dried and processed as above (grinding, melting, and extrusion) to create similarly shaped 15-mm or 7-mm × 2-mm diameter rods; the 15-mm rods matched the dimensions of previously engineered silicone-based rods [ 21 , 26 , 27 ]; note that the surface area of two 7-mm rods equaled that of a single 15-mm rod.…”

“…Acetonitrile (900 μ L) was added to each 100 μ L aqueous sample (DPBS or DMEM) for drug release determination by HPLC as previously described [ 26 , 27 ]. The amount of drug in each sample was determined through HPLC and UV spectrophotometry against a 15-point standard curve, as previously described [ 26 , 27 ].…”